Methods for making and administering a blinded oral dosage form and blinded oral dosage form therefor

ABSTRACT

The invention relates to a method for making and administering a blinded oral dosage form and the blinded oral dosage form therefor, used for disguising the identity of tableted medications. The method includes making a blinded oral dosage form by placing a tableted medication within a capsule have a diameter greater than its height. The blinded oral dosage form is the combination of the above-described capsule and the tableted medication.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method for making and administering ablinded oral dosage form and the blinded oral dosage form therefor, usedfor disguising the identity of tableted medications.

2. Description of the Prior Art

Over the years, various methods and devices have been used to compareone medication with another to determine the relative safety and/orefficacy of the medication. It is a common practice to disguise themedications in order to prevent any prejudice from investigatorsadministering the drugs and subjects ingesting the drugs. Disguisingmedications from investigators administering or subjects ingesting themedication is commonly referred to as "blinding".

Tableted medications are normally "blinded" by placing the medication inelongated cylindrical, i.e., tubular, opaque gelatin capsules along withinactive packing materials. In this way, none of the tabletedmedications can be identified by the investigators administering themedication or subjects ingesting the medication. However, conventional"blinding" procedures using elongated cylindrical gelatin capsules havespecific limitations when using certain tablets since the diameter ofthe tablet is often very large in relation to the diameter of thecapsule.

Elongated cylindrical, or tubular, gelatin capsules may be purchased instandard sizes having a body portion and a cap portion. The capsulestypically have an elongated cylindrical shape with rounded ends thatfacilitate the swallowing of the capsule. Standard elongated cylindricalcapsules may be purchased in various sizes. However, the diameter of thecapsule is typically small in relation to the length or height of thecapsule.

For example, ELANCO Qualicaps™, which are typical of the industry, areavailable in the following sizes: 000, 00, 0EL, 0, 1, 2, 3, 4 and 5. Thedimensions of these capsules are provided in the following table.

    __________________________________________________________________________    DIMENSIONS OF ELANCO QUALICAPS ™                                                CAP    BODY   CAP    BODY  FILL.sup.1                                         DIAMETER                                                                             DIAMETER                                                                             LENGTH LENGTH                                                                              LENGTH                                        SIZE (MM)   (MM)   (MM)   (MM)  (MM)                                          __________________________________________________________________________    000  9.88   9.5    13.1   22.0  26.1                                          00   8.51   8.15   11.7   20.2  23.5                                          0EL  7.63   7.33   12.0   20.7  24.0                                          0    7.63   7.33   10.9   18.5  21.8                                          1    6.90   6.62   9.7    16.5  19.5                                          2    6.35   6.07   8.9    15.1  17.8                                          3    5.82   5.56   7.9    13.3  15.8                                          4    5.32   5.06   7.2    12.3  14.5                                          5    4.9    4.67   6.0    9.1   11.7                                          __________________________________________________________________________     .sup.1 FILL LENGTH is the recommended filled joined length of ELANCO          POSILOK ™ capsules which is controlled by the location of the locking      features on the cap and body.                                            

As listed, such capsules have a length to diameter ratio of well overtwo but less than three.

In contrast, tableted medications commonly used in the pharmaceuticalindustry are manufactured in various shapes and sizes. One common shapeused for tableted medications is the disk-shaped tablet. The diameter ofthese tablets is usually large in relation to the length or height ofthe tablet. Consequently, when investigating or comparing medications,one of which is in a tablet form, the investigator must obtain a capsulelarge enough to facilitate the diameter of the largest tablet used inthe study. That is, the cylindrical or tubular capsule into which thetableted medication must be placed for purposes of blinding, must have alarger diameter than the diameter of the tablet. Alternatively, thetableted medication must be broken into small pieces or particles toplace the medication into the capsule.

A standard elongated capsule having a diameter larger than the diameterof the tableted medication has a length at least two times longer thanthe diameter of the tableted medication. For example, a tabletedmedication having a diameter of 9 millimeters would have to beencapsulated in an 000 ELANCO Qualicap™. The fill length of the ELANCOQualicap™ is 26.1 millimeters. Consequently, the standard elongatedcylindrical capsules are much longer than necessary.

One concern that arises with respect to the ingestion of medication isthat the elongated cylindrical capsules large enough to encapsulatevarious tableted medications are so large that they are not as easilyswallowed as the tableted medication itself. This is especiallyimportant when administering such medication to infants, children andthe elderly who often have difficulty swallowing medication.

Another concern that arises with respect to the ingestion of medicationis that elongated cylindrical capsules can accidently be swallowedsideways which causes the capsule to enter the esophagus lengthwise.This produces difficulty in swallowing and significant discomfort to thesubject ingesting the capsule. This is especially important whencylindrical-shaped capsules are presented to animals as it is sometimesnecessary to push the capsule down the throat of the animal.

Another concern that arises with respect to the ingestion of medicationis that there are no readily available cylindrical capsules that may beused to encapsulate tableted medications having a large diameter. Forexample, a tableted medication having a diameter of 10 millimeters ormore could not be encapsulated in even the largest ELANCO Qualicap™which has a diameter of 9.5 millimeters. Tableted medications having adiameter of 10 millimeters or more are common. Such medications areillustrated in the Physician's Desk Reference, 43rd Edition, MedicalEconomics Company, Inc., Oradell, N.J. (1989) and in The FamilyPhysician's Compendium of Drug Therapy, McGraw-Hill Book Company, NewYork (1988) both of which contain actual size, full-color reproductionsof various medications available from various manufacturers.

Of course, tableted medications could be broken into smaller pieces orused in smaller sizes; however, breaking tableted medications or usingthem in smaller sizes affects the actual kinetics of medication. Inparticular, when tablets are broken up into smaller sizes there is moresurface area for dissolution and absorption of the medication.Furthermore, many tableted medications have various coatings which willbecome ineffective if destroyed. Consequently, the integrity of theinvestigation or comparison is compromised when breaking up the tabletedmedications.

Thus, in the majority of research studies, a "double-dummy" approach isused when encapsulation is not practical. The "double-dummy" approachcould best be exemplified in a study in which two or more tablets ofvarying size (for instance, one large and one small) are compared forsafety or efficacy. When the larger of two tablets is of too great adiameter to be placed inside the standard elongated capsule, it becomesnecessary to produce placebos for both the large and small tablets. The"double-dummy" procedure requires the subject to ingest two tablets (oneactive and one placebo). Therefore, when taking a large tablet as activemedication, the subject must also take a smaller tablet as a placebo andvice versa. This method allows the investigator and the subject takingthe medicine to be blinded as to whether the larger tablet is an activemedication or, alternatively, a placebo.

Many variations of the "double-dummy" procedure exist. However, allvariations require the expense of developing placebos identical to testmedications or obtaining the placebo from the manufacturer of the activeproduct. Furthermore, it should be noted that the use of two or moretablets in a "double-dummy" procedure requires the subject to ingestseveral pills at each dosing period. The ingestion of two or more pillsinherently results in a significant placebo effect which may increase(or, alternatively, decrease) the perceived efficacy (or side effect)profile of the study medication. In addition, ingesting multiple pillsmay affect the actual kinetics of the study medication.

While various unconventionally shaped capsules are known in the art, thecapsules are either not used to blind tableted medications and/or arenot convenient for blinding tableted medications. Such variousunconventionally shaped capsules are disclosed in U.S. Pat. Nos.462,990; 710,060; 730,643; 1,087,843; 1,148,621; 2,196,283; and4,774,092.

U.S. Pat. No. 462,990 discloses a capsule consisting of a soluble shellor casing formed integrally with a soluble partition to provideseparated chambers for different kinds of medicine. This patent does notdisclose a method for blinding tableted medications. In fact, thecapsules are not suitable for blinding tableted medications since theyare not constructed in a manner that permits tableted medication ofvarious sizes and shapes to be placed therein.

U.S. Pat. No. 710,060 discloses a capsule in which one piece is providedwith a double wall construction and the other piece a single wallconstruction. The patent mentions nothing with respect to placing atableted medication within the capsule.

U.S. Pat. No. 730,643 discloses a tableted medication contained within agelatin casing. The tableted medication is enclosed within the casingalong with a liquid ingredient for introducing the solid and liquidsimultaneously. The device shown in U.S. Pat. No. 730,643 is notacceptable for blinding procedures since the casing containing theliquid and solid ingredients is formed with various presses and diesresulting in an integrally formed-one piece sphere.

U.S. Pat. No. 3,536,074 discloses a tableted medication within a liquidimpervious frangible sac. The tableted medication is enclosed within thefrangible sac along with a liquid ingredient to assist in the swallowingof the tableted medication. The device shown in U.S. Pat. No. 3,536,074is not acceptable for blinding procedures since the frangible saccontaining the liquid and solid ingredients is an integrally-formed onepiece unit.

The devices disclosed in U.S. Pat. Nos. 730,643 and 3,536,074 areunacceptable for blinding studies since the manufacture of such devicesrequires manufacturing equipment for placing the tablet and liquidwithin the capsule and for sealing the capsule.

The above-described methods and devices are intended to provide a meansfor "blinding" medications from investigators and subjects taking themedications. However, as described above, there are many disadvantagesassociated with these methods. Such disadvantages include the fact thatelongated cylindrical or tubular shaped capsules readily available tothose in the art are not convenient for disguising many tabletedmedications due to their inability to contain many of the largertableted medications and the unsatisfactory nature of the alternativemethods which are commonly utilized.

Thus, there remains a long felt need in the art for an improved methodand device for "blinding" tableted medications containing an activesubstance. Such method would facilitate the investigation of variousmedications to determine their physiological or pharmacological effectas well as to compare the safety and/or efficacy of the medications withother medications.

SUMMARY OF THE INVENTION

It is, therefore, a primary object of the present invention to providean improved method for conducting a blinded study, an improved methodfor blinding a tableted medication and an improved dosage formcomprising a tableted medication within a capsule such thatinvestigators analyzing such dosage form and subjects ingesting suchdosage form cannot determine the identity of the medication they areadministering or ingesting.

Another object of the present invention is to provide a method forcoating a tableted medication by encapsulating the tableted medicationin a capsule More readily adapted for tableted medications. The methodallows researchers and pharmacists to provide medications with one ormore desirable coatings without having to specially order the tabletedmedication with the desired coating.

Still another object of the present invention is to provide a coveringfor a tableted medication without the need for special coatingequipment, i.e. a capsule having a shape that can be more readilyswallowed than a conventional capsule that is large enough toencapsulate the tableted medication.

Yet another object of the present invention is to provide a method forcoating a capsule with conventional tablet coating apparatus and byconventional tablet coating procedures.

Still another object of the present invention is to provide a capsulehaving a shape that can be more readily swallowed than a conventionalcapsule that is large enough to "encapsulate" a large tablet. Theblinded oral dosage form of the present invention does not need to besignificantly larger than the tablet itself, in both diameter andthickness, and could therefore be as easily swallowed as the tabletitself. Thus, the blinded oral dosage form of the present invention maybe transported through the esophagus more easily than a readilyavailable elongated cylindrical capsule that would be required todisguise the same tablet.

Consequently, another object of the present invention is to provide ablinded oral dosage form that is more easily swallowed by people whoexperience difficulty in swallowing capsules than a readily availableelongated cylindrical capsule that would be required to disguise thesame tablet.

Another object of the present invention is to provide a blinded oraldosage form that could be used for blinding conventional Medications andwhich is resistant to tampering.

The method for conducting a blinded study comprises making a firstblinded oral dosage form by placing a first composition within a capsulehaving a body portion and a cap portion such that the diameter of thecapsule is greater than its height when closed. The Method also includesmaking a second blinded oral dosage form by placing a second compositionwithin a substantially identical capsule and then closing the capsule.The method also includes administering the first blinded oral dosageform to a subject and administering the second blinded oral dosage formto the same subject or to another subject.

Accordingly, the method for blinding a tableted medication comprisesplacing the tableted Medication within a capsule having a body portionand a cap portion such that the diameter of the capsule is greater thanor equal to its height when closed.

Specifically, the method for blinding a tableted medication comprisesplacing the tableted medication within a capsule having a body portionand cap portion and then closing the capsule, wherein the body portioncomprises an open end and an oppositely positioned closed end. The openend is defined by a circumferential edge lying in a first plane. Thebody portion is configured such that the greatest straight line distanceconnecting two points on the circumferential edge is greater than theperpendicular distance between the first plane and a second plane whichcontacts an outer surface of the closed end of the body portion andwhich is parallel to the first plane. Preferably, the cap portion isconfigured similarly to the body portion. Even more preferably, themethod includes the use of a cylindrical capsule having interlockingcylindrical body and cap portions.

The dosage form of the present invention comprises a capsule and, withinthe capsule, a tableted medication. The capsule has an interlocking bodyportion and cap portion and a diameter greater than its height whenclosed.

More specifically, the dosage form comprises a capsule and, within thecapsule, a tableted medication, wherein the capsule comprises aninterlocking body portion and cap portion. The body portion comprises anopen end and an oppositely positioned closed end. The open end isdefined by a circumferential edge lying in a first plane. The bodyportion is configured such that the greatest straight line distanceconnecting two points on the circumferential edge is greater than theperpendicular distance between the first plane and a second plane whichcontacts an outer surface of the closed end of the body portion andwhich is parallel to the first plane. Preferably, the cap portion isconfigured similarly to the body portion. Even more preferably, thedosage form comprises a capsule and, within the capsule, a tabletedmedication, wherein the capsule comprises interlocking cylindrical bodyand cap portions.

Even more specifically, the dosage form of the present inventioncomprises the combination of a tableted medication and a capsule, thecapsule including a body portion and a cap portion. The cap portion andthe body portion each are hollow and have an open end with means whichinterfit with one another so that the body portion and the cap portioncan be brought towards one another along an axis with their open endsfacing one another and connected to one another to define the capsule.The capsule has a cavity formed by the hollow body portion and thehollow cap portion and the tableted medication is disposed within thecavity. The capsule has a length or height as measured along the axisand a diameter as measured perpendicular to the axis, the height Of thecapsule being less than the diameter of the capsule as measured from anouter surface Of the capsule.

BRIEF DESCRIPTION OF THE DRAWINGS

The features of the present invention will become apparent from thedescription, considered in conjunction With the drawings, in which likeelements bear like reference numerals and wherein:

FIG. 1 is a perspective view of one embodiment of the capsule of theblinded oral dosage form of the present invention illustrating thecapsule;

FIG. 2 is a perspective view of the capsule shown in FIG. 1 illustratingtwo portions of the capsule separated from one another;

FIG. 3 is a cross-sectional view of the embodiment of the blinded oraldosage form illustrated in FIG. 1 with a tableted medication enclosedwithin the capsule;

FIG. 4 is a perspective view of another embodiment of the blinded oraldosage form employing a different form of interlocking mechanism forinterlocking the two portions; and

FIG. 5 is a perspective view of another embodiment of the blinded oraldosage form employing a different form of interlocking mechanism forinterlocking the two portions.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The following description of various embodiments of the dosage form,methods of making the dosage form and methods of administering thedosage form are merely illustrative of the present invention and theyshould not be considered as limiting the scope of the invention in anyway, as these illustrations and other equivalents thereof will becomemore apparent to those versed in the art in the light of the presentdisclosure, and the accompanying claims.

The method for conducting a blinded study comprises making a firstblinded oral dosage form by placing a first composition within a capsulehaving a body portion and a cap portion such that the diameter of thecapsule is greater than its height when closed. The method also includesmaking a second blinded oral dosage form by placing a second compositionwithin a substantially identical capsule and then closing the capsule.The method also includes administering the first blinded oral dosageform to a subject and administering the second blinded oral dosage formto the same subject or to another subject.

Accordingly, the Method for blinding a tableted medication comprisesplacing the tableted medication within a capsule having a body portionand a cap portion such that the diameter of the capsule is greater thanits height when closed.

The blinded oral dosage form of the present invention includes a capsulehaving a body portion and a cap portion which interlock to form anenclosed space or cavity referred to herein as the volume of thecapsule. Prior to interlocking the cap portion with the body portion,one or more tableted medications are placed within the body portionalong with any desired non-toxic, pharmaceutically acceptable fillermaterial sufficient to prevent substantial movement of the tablet withthe capsule. Optionally, only non-toxic, pharmaceutically acceptablefiller material is placed with the capsule to form a placebo. Once thetablet or tablets and/or filler material is placed inside the bodyportion and the cap portion is interlocked with the body portion, thetablet or tablets and/or the filler material is blinded to personsadministering and subjects ingesting the blinded oral dosage form.

Referring initially to FIG. 1, the capsule includes a cap portion 15 andbody portion 20 of the blinded oral dosage form of the present inventionproduced in such a way to allow the cap portion 15 and body portion 20to be combined by fitting the one into the other with sufficiently closetolerances to produce what is essentially a friction lock.

Generally, the capsule comprises a cross-sectional dimension D and aheight or length R. The cross-sectional dimension D, when the capsulehas a circular cross-section surface, is the diameter of thecross-section. In instances where the cross-sectional surface is notcircular, the cross-sectional dimension D is the greatest straight linedistance connecting two points on the edge of the cross-sectionalsurface. Preferably, however, the cross-sectional surface is circular.Nonetheless, as used herein, the term "diameter" is the greateststraight line distance connecting two points on the edge of thecross-sectional surface. This distance is also referred to herein as thecross-sectional dimension D. The height or length H is the distance fromthe top of the capsule to the bottom of the capsule in a directionperpendicular to the cross-sectional dimension D. Preferably, thecross-sectional dimension D is greater than the height or length R,preferably much greater.

As shown in FIG. 2, the cap portion 15 comprises an open end 25 and anoppositely positioned closed end 30. The open end is defined by acircumferential edge 35 which lies in a first plane 40. Opposite theopen end 25, there is a closed end 30 having a point or surface 45touching but not intersecting a second plane 50 which is parallel to thefirst plane 40. The greatest straight line distance connecting any twopoints on the circumferential edge 35 is greater than the perpendiculardistance between the first plane 40 and the second plane 50. That is,the cross-sectional dimension D is greater than the height H of the capportion is.

Likewise, the body portion 20 comprises an open end 55 and an oppositelypositioned closed end 60. The open end is defined by a circumferentialedge 65 which lies in a first plane 70. Opposite the open end 55 thereis a closed end 60 having a point or surface 75 touching but notintersecting a second plane 80 Which is parallel to the first plane 70.The greatest straight line distance connecting any two points on thecircumferential edge 65 is greater than the perpendicular distancebetween the first plane 70 and the second plane 80. That is, thecross-sectional dimension D is greater than the height u of the bodyportion 20.

Tablets of various sizes and shapes along with sufficient non-toxic,pharmaceutically acceptable filler material (to avoid the tabletrattling within the capsule) may be placed within cap 15 or body 20portions; however, the largest tablet must be minimally smaller than therespective opening in order for the tablet to be placed within thecapsule. Optionally, only non-toxic, pharmaceutically acceptable fillermaterial is placed within a capsule to form a placebo. In addition,various powdered medications or liquid medications could be placedwithin a capsule to form a comparative dosage form.

Normally, for human applications, tablets have a diameter ranging fromabout 2 to about 16 millimeters, preferably about 5 to about 12millimeters, with a thickness ranging between about 1 and about 10millimeters, preferably about 2 to about 7 millimeters.

Thus, for human applications, it is contemplated that thecross-sectional dimension D, i.e., the greatest straight line distancebetween two points on the circumferential edge of the cap or bodyportions of the capsule, could range from about 3 to about 18millimeters, preferably about 3 to about 13 millimeters. In addition, itis contemplated that the overall length or height H of the capsule,i.e., the distance between the point or surface 45 touching the secondplane of the cap and the point or surface 75 touching the second planeof the body when the body and cap are interlocked, could range fromabout 3 to about 11 millimeters, preferably about 3 to about 7millimeters. However, the cross-sectional dimension D should be greaterthan or equal to the length or height H. Preferably, the cross-sectionaldimension D is greater than the length or height H. Even morepreferably, the cross-sectional dimension D is at least 1.5 timesgreater than length or height H. Most preferably, the cross-sectionaldimension D is at least 2.0 times greater than the length or height H.

Another preferred embodiment of the invention for human applicationswould have a diameter D between about 4 and about 14 millimeters and aheight or length H between about 3 and about 8 millimeters. In this way,tablets of normal size (3 to 13 millimeters in diameter and 2 to 7millimeters in thickness) may be contained within the blinded oraldosage, allowing for packing materials to avoid movement of the tabletwithin the device.

Another preferred embodiment of the blinded oral dosage of the presentinvention includes a capsule having a diameter D that is larger than thediameter of the standard elongated cylindrical capsules. Specifically,this preferred embodiment has a diameter of at least about 10millimeters, or even a capsule having a diameter of at least about 11 orabout 12 millimeters. Such preferred capsules are particularly suitablefor encapsulating tableted medications having a diameter larger than thediameter of standard elongated cylindrical capsules. Tabletedmedications having a diameter of at least 10 millimeters include the 400mg dosage of Motrin° brand ibuprofen tablets, the 500 mg dosage ofMaximum Strength Anacin® brand analgesic (aspirin/caffeine) tablets, the250 mg dosage of Wyamycin®S brand erythromycin stearate tablets, the 500mg dosage of Aralen® Phosphate brand chloroquine phosphate tablets, the500 mg dosage of Tolinase® brand tolazamide tablets as well as manyother widely available medications. Other tableted medications having adiameter of at least 10 millimeters are illustrated in the Physician'sDesk Reference, 43 rd Edition, Medical Economics Company, Inc., Oradell,N.J. (1989) and in The Family Physician's Compendium of Drug Therapy,McGraw-Hill Book Company, New York (1988) both of which contain actualsize, full-color reproductions of various medications available from avariety of manufacturers.

The device illustrated in FIG. 2 further includes a female frictionportion 85 for placing on top of and interlocking with the male frictionportion 90 of the body portion of the device. The female frictionportion 85 of the device for the above-described human applications maybe between about 1 and about 10 millimeters long, preferably betweenabout 1 and about 5 millimeters long. The male friction portion 90 ofthe device may have dimensions similar to that of the female frictionportion 85.

As shown, the cap portion 15 and the body portion 20 of the capsule mayhave rounded closed ends. The radius 95 of the cap portion or the radius100 of the body portion of the device may be, for human applications,between about 1 and about 9 millimeters. The radius is the distance fromthe midpoint of the area defined by the circumferential edge to theinside surface of the closed end of the respective portion. The radiusis not uniform in most instances from the midpoint of the area definedby the circumferential edge to various points on the inside surface ofthe closed end. That is, the distance from the midpoint to one point onthe inside surface may not be the same as the distance from the midpointto a different point on the inside surface. Rounded closed ends arepreferred to facilitate ease of swallowing.

FIG. 3 shows a top view with midline cut-away illustrating a cylindricalor disk-shaped blinded oral dosage form complete with the tablet 10contained within the capsule 5. As shown, there may be a certain amountof space 105 within the cavity formed by interlocking the cap portionand body portion for placement of the non-toxic, pharmaceuticallyacceptable filler material. The filler material may keep the tablet fromrattling inside the capsule and giving away its existence. Optionally,only non-toxic, pharmaceutically acceptable filler material is placedwithin the capsule to form a placebo.

A preferred distance from the edge of the tablet to the inside edge ofeither the cap or the body portion of the device for the above-describeddevices suitable for human applications may be from about 0.1 to about 6millimeters. Preferably, one or more tablets occupy at least 20 percentof the enclosed space or cavity of the capsule. More preferably, one ormore tablets occupy at least 35 percent of the enclosed space of thecapsule. Even more preferably, one or more tablets occupy at least 50percent of the enclosed space of the capsule. Even more preferably, oneor more tablets occupy at least 75 percent of the enclosed space. Evenmore preferably, one or more tablets occupy at least 90 percent of theenclosed space.

As the two parts of the capsule are placed together (covering thecontents), the friction produced by the close tolerances between the twosegments should be sufficient to keep the parts from disassociatingduring transportation and normal use. In addition, it should besufficiently difficult to open the product to inhibit research subjectsor investigators from attempting to determine the contents.

While the above-described illustrations describe preferred embodimentsof the blinded oral dosage of the present invention, it should be notedthat the device may be of any shape and size. Thus, the circumferentialedge of either the cap portion or body portion of the capsule could becircular, ellipsoidal, square, rectangular, triangular or any othercircumferential multi-sided shape as well as any other circumferentialcurvilinear shape. Likewise, while the above illustrations show roundedclosed ends of the cap portion and the body portion, the closed endscould have flat surfaces.

Most preferably, the capsules of the present invention are of acylindrical or disk shape with rounded ends. However, by use of the term"cylindrical", when referring to the capsules of the present invention,it is meant that the capsules when assembled are "non-elongated". Thephrase "non-elongated" when referring to the preferred cylindricaldevices of the present invention, means that the diameter D of thedevice is greater than or equal to the length or height H, i.e., thestraight line distance from end point to end point, of the capsule. Morespecifically, the preferred blinded oral dosage of the present inventionhas a non-elongated cylindrical shape wherein the ends of the cylinderare rounded or without edges as illustrated in FIGS. 1-5. In contrast,commercially available capsules are elongated. That is, the length orheight of commercially available capsules is greater than the diameter.Typically, the length to diameter ratio of commercially availablecapsules is between two and three.

Thus, as used herein, an "elongated cylindrical shape" refers to theshape of standard cylindrical capsules widely used in manufacturingencapsulated medications. Such standard elongated cylindrical shapedcapsules typically have rounded ends and have a length or height longerthan its diameter. Examples of medications available in capsules havingan elongated cylindrical shape include THEOBID® capsules, TRINSICON®capsules, VICONFORTE® capsules, AMOXIL® capsules, BACTOCILL® capsules,CLOXAPEN® capsules, DYCILL® capsules, TIGAN® capsules, DECONAMINE®capsules, MEXITIL® capsules, R-TUSS° capsules, MIDRIN® capsules,ACTIFED® capsules, SUDAFED° capsules, ZOUIRAX® capsules, BRONTRIL®capsules, HYDROCET® capsules and MIDRIN® capsules. Each of theabove-listed capsules as well as others are available via variousmanufacturers as set forth in the Physicians Desk Reference, 43rdEdition, Medical Economics Company, Inc., Oradell, N.J. (1989) .

The widely available elongated cylindrical capsules are also shown inRemington's Pharmaceutical Sciences, 18th Edition, on Page 1658 at FIG.89-34, Mack Publishing Company, Easton, Pa. (1990).

The widely available elongated cylindrical capsules are also availableempty and ready for filling. Elongated cylindrical capsules availableempty and ready for filling include the ELANCO QUALICAPS™ referred toabove.

In contrast to the elongated cylindrical capsules, the capsules of thepresent invention have a length (i.e. height) to diameter ratio lessthan or equal to one. Nonetheless, the dimensions of the blinded oraldosage of the present invention may be of any size depending on theapplication, just so long as the height to diameter ratio does notexceed one. For example, when administering the blinded oral dosage ofthe present invention to large animals, such as cattle or horses, largerdosage forms may be required. Of course, logic dictates that the size ofthe blinded oral dosage form depends both on the size of the tablet andthe size of the subject ingesting the dosage. Thus, any variety of sizesare applicable to the present invention. However, the cross-sectionaldimension D should be greater than or equal to the length or height H.Preferably, D is greater than the height H.

The tablets placed within the enclosed cavity of the blinded oral dosageform of the invention may be any one of a wide variety of tabletedmedications. Tableted medications are medications that have been pressedor otherwise formed into a solid dosage form ready for ingestion. Thetableted medication may be any number of a wide variety of shapescurrently available to those skilled in the art. In this regard,manufacturers of tableted medications manufacture such tablets in roundor cylindrical shapes, square shapes, rectangular shapes, triangularshapes, oval shapes, spherical shapes, hexagonal shapes, trapezoidalshapes, etc. Accordingly, any such tablet or tablet shape is suitablefor placing within the cavity of the blinded oral dosage form.

When the cap portion is engaged with the body portion of the instantdosage form, an enclosed cavity is formed such that the contents of thedevice are not exposed to external elements present duringtransportation and handling of the dosage forms. The volume of thecapsule is the enclosed cavity formed by the cap and body portions ofthe capsule. The cap portion may engage the body portion via any lockingmechanism known in the art. Locking mechanisms are particularlyimportant in research studies as they inhibit volunteers (as well asresearchers) from opening capsules and discovering their contents priorto administration. They are also important in simply keeping the twohalves of the product from falling apart during storage, transportationor usage.

Locking mechanisms may include, for example, friction-type lockingmechanisms as shown in FIGS. 1 and 2. The friction-type lockingmechanism includes friction produced by the close tolerance between themale and female segments of the capsule.

FIG. 4 is an illustration of another embodiment of the blinded oraldosage form showing a tongue and groove locking mechanism. In thisconfiguration, the body portion 20 of the device has accordion-shapedridges 110 permitting it to move into the cap portion 15 of the devicesuch that it interlocks with one or more internal indentations 115. Asshown, one or more internal indentations 115 or ridges 110 may be used.Optionally, the cap portion could contain the ridges and the bodyportion could contain the internal indentations of the lockingmechanism.

If the male section has two or more internal indentations or ridges, anyone of the ridges could be locked onto depending on the thickness of thetablet contained inside. This would allow the tablet-shaped capsule tohave one, two or more thicknesses to accommodate tablets of variousthickness or even multiple tablets being encapsulated within theproduct. Obviously, for any given study, all tablet-shaped capsuleswould be of identical thickness, with more or less filler presentdepending upon the space occupied by the tablet(s) encapsulated.

The cross-section of the ridges or the internal indentation may have aprofile which is curved or angular, and may range in shape, for example,from a single to a multiple radius design, or from a V-shape to amulti-angular shape, such as for example a square, rectangular,trapezoidal, etc. shapes. Examples of such tongue and groove-typelocking mechanisms are illustrated in U.S. Pat. No. 4,882,618.

As with the "tongue and groove" and "friction" locking mechanisms, a"flexible lip" could also be used as a means of maintaining theintegrity of a tablet-shaped capsule as described above. FIG. 5 providesan illustration of another embodiment of the oral dosage form of theinvention containing a flexible lip type locking mechanism. In thisform, the cap portion 15 of the device would fit over the body portion20 of the device or vice versa. Both the cap and body portions of thedevice contain a portion of the "flexible lip" locking mechanism. Eachportion of the locking mechanism is rounded on the edge in such a way asto allow the body portion 20 of the locking mechanism (which is slightlysmaller) to slip into the cap portion 15 of the locking mechanism. Thelarger rounded edge of the cap portion 15 of the locking mechanism issufficiently flexible to expand and slip over the smaller but similarlyrounded edge of the body portion 15 of the locking mechanism and due tothe overlap, lock both segments together.

Additional locking mechanisms could include screw-type lockingmechanisms and external fasteners. Accordingly, any locking mechanism inexistence for standard capsule shapes could be utilized for the blindedoral dosage of the present invention as long as it insures the integrityof the dosage form during normal handling.

Additionally, it is noted that each of the above-mentioned lockingmechanisms may allow locking of the capsules at various thicknesses sotablets of various thicknesses could be encapsulated along with fillers.

The blinded oral dosage form may also include various wraps or tapesconventionally used with standard gelatin capsules to insure that thedevice is not tampered with prior to administration. It may be desiredto apply a sealing band to an assembled dosage form, to prevent leakagein the case of any possible powder or liquid fillings, or to render thecapsule tamper-evident or tamper resistant or for identificationpurposes. This may be achieved using known methods and equipment, suchas, for example, the Quali-Seal machine (Manufacturing Chemist, January,1987, p. 27).

Preferably, the body and cap portions of the blinded oral dosage form ofthe present invention are made of a hard gelatin and could bemanufactured on existing equipment with modifications to dies and otherparts of those or similar machines. Optionally, the capsules of thepresent invention could be made of soft gelatin or any other materialused to make conventional capsules.

By way of illustration, hard gelatin capsules may be made in two partsby dipping stainless steel pins into a molten gelatin solution, andallowing the gelatin to set and dry. It is generally known that thegelatin film, as it dries, also undergoes shrinkage. The shrinkagedepends on a number of factors such as the amount of water to beeliminated, the gelatin used, the drying regime and the number and typeof additives such as dyes, other colorants, opacifiers, plasticizers,viscosity builders or surfactants which may be included within thegelatin compositions of the present invention. Such processes andcompositions are well known in the art, for example, see The Theory andPractice of Industrial Pharmacy, 3rd Ed., Lea & Febiger, Philadelphia(1986) and Remington's Pharmaceutical Sciences, 18th Edition, MackPublishing Company, Easton, Pa. (1990).

In addition, the body and cap portions of the blinded oral dosage formmay be made of materials that are soluble in alkaline intestinalsecretions but substantially insoluble in and resistant to acidsecretions of the stomach. Such materials are commonly referred to ashaving enteric properties. The enteric dosage forms may be made, forexample, by dip-molding using a homogeneous film-forming mixturecomprising (1) gelatin and an ammonium salt of hydroxypropylmethylcelluose phthalate polymer, or (2) hydroxypropyl methylcelluoseand an ammonium salt of cellulose acetate phthalate polymer, or (3)gelatin and an ammonium salt of a copolymer of methacrylic acid andmethacrylic acid ester optionally in combination with additionalingredients such as plasticizers, surfactants and coloring agents. Theabove compositions are described, for example, in more detail in U.S.Pat. No. 4,138,013.

Likewise, many other ingestible materials may be used to make the capand body portions of the blinded oral dosage form of the presentinvention. Preferably, however, the capsules are made of a hard gelatincomposition.

As a result of the non-elongated shape of the blinded oral dosage form,it is also suitable for coating with pharmaceutical grade materials instandard tablet coating bins (unlike a standard elongated shaped capsulewhich does not tumble appropriately for coating purposes). The dosageforms of the present invention may tumble exactly like a standard tabletand may thereby coat as easily as any tablet depending on the particularembodiment. Coatings (or multiple coating layers) of various degrees ofhardness, thickness or solubility would be aesthetically pleasing andhave standard pharmaceutical qualities regarding dissolution rate, easeof swallowing and manufacturing advantages.

Preferred embodiments of the blinded oral dosage form could be coated bya standard tablet coating process such as described, for example, inRemington's Pharmaceutical Sciences, 18th Edition, Chapter 90, "CoatingOf Pharmaceutical Dosage Forms", Mack Publishing Company, Easton, Pa.(1990).

In addition to the above advantages, one or more coatings may provide a"tamper proof" blinded oral dosage form as opening would break thecoating. The broken coating material would be difficult, if notimpossible, to restore to its original character and would be an obvioussignal to the investigators or subjects ingesting the device not to usethe product. The break could be made more obvious in many ways includinguse of layered coverings of different colorings, highly friable coatingmaterials or unusual colors. The coating could also help maintain theintegrity of the product during both research and commercial use. Also,the coating may be used in conjunction with an external wrap or tamperresistant tape that protects the device. Additionally, it is alsopossible to utilize a number of coating compounds or active agents inthe coating composition to achieve a desired effect. For instance, anenteric coating can be applied as one layer or in combination withanother coating solution.

The method of the present invention includes preparing blinded tabletedmedications. In particular, the method includes disguising a tabletedmedication by placing the medication in a non-elongated capsule, i.e., acapsule of the present invention having a cross-sectional dimension Dgreater than or equal to its length or height H.

This method provides a means for disguising tableted medications in acapsule more readily adapted for tableted medications. Thus, standardelongated capsules which are overly large in relation to the tabletedmedications are not necessary. In fact, the method includes disguisingone or more tablets that occupy at least 20 percent, more preferably atleast 35 percent, more preferably at least 50 percent, more preferablyat least 75 percent or most preferably at least 90 percent of theenclosed space or cavity of the capsule.

The method may further include placing one or more non-toxic,pharmaceutically acceptable filler materials within the cavity of thecapsule to prevent the tablet from rattling inside the capsule. Thisprevents researchers or subjects from distinguishing between capsulescontaining tablets of various sizes, or between those containing tabletsand those containing non-tableted medications or fillers only (i.e.,placebos). Optionally, only non-toxic, pharmaceutically acceptablefiller is placed within the capsules of the present invention to form aplacebo. Suitable non-toxic, pharmaceutically acceptable fillermaterial, including sugars and starches, would be apparent to thoseskilled in the art.

Additionally, the method may further include applying one or morecoatings covering the capsule. Certain coatings may be applied eitherbefore or after the tablet is placed within the capsule. In the casewherein the capsules are precoated, the method of the present inventionincludes a simple and easy means for encapsulating a tableted medicationto provide a desired coating without the need to coat the tablet itself.In the case wherein the capsules are coated after filling, the closedcapsule, unlike standard elongated capsules, may be coated according toconventional tablet coating tumble processes and in conventional tabletcoating equipment.

Furthermore, the method of the present invention is particularlysuitable for comparing two different medications, i.e., one tabletedmedication and another medication which may or may not be tableted.Comparing two different medications would include making a first blindedoral dosage form by disguising a first tableted medication in anon-elongated capsule and making a second blinded oral dosage form bydisguising a second medication (either tableted or not) in anon-elongated capsule having substantially the same size and shape asthe first blinded oral dosage form.

Thus, the method of the present invention further provides a means fordisguising or blinding one or more medications of different shapes andsizes, e.g., one large and one small, or even the same medication indifferent forms or amounts. The method in such case may include placingthe large tableted medication in a capsule of the present invention oflarge enough size to hold the tableted medication and placing a smallertableted medication in a capsule identical to the capsule in which thelarger tableted medication was placed. In this way, the personconducting the clinical trial and the subject ingesting the blinded oraldosage would not know what medication, form of medication or amount ofmedication was administered. By use of this method, two medications ofsubstantially different size or shape or the same medication indifferent forms or amounts could be readily compared.

The method of the present invention is also suitable for analyzing onetableted medication as compared to a second dosage form which does notcontain an effective medication. Analyzing one tableted medication mayinclude making a first blinded oral dosage form by disguising a firsttableted medication in a non-elongated capsule and making a secondblinded oral dosage form having substantially the same size and shape asthe first blinded oral dosage that does not contain an effectivemedication, i.e., a placebo.

From the foregoing description, one of ordinary skill in the art caneasily ascertain the essential characteristics of the instant invention,and without departing from the spirit and scope thereof, can makevarious changes and/or modifications of the invention to adapt it tovarious usages and conditions. As such, these changes and/ormodifications are properly, equitably and intended to be, within thefull range of equivalents of the following claims.

What is claimed is:
 1. A method for blinding a tableted medicationcomprising placing said tableted medication within a cylindrical,ingestible capsule effective for administering a tableted medicationhaving interlocking cylindrical body and cap portions, said body portioncomprising an open end and an oppositely positioned closed end, saidopen end being defined by a circumferential edge, said circumferentialedge lying in a first plane, said body portion being configured suchthat the greatest straight line distance connecting two points on saidcircumferential edge is greater than the perpendicular distance betweensaid first plane and a second plane which contacts an outer surface ofthe closed end of the body portion and which is parallel to the firstplane; and then closing the capsule.
 2. The method as claimed in claim1, wherein said cap portion comprises an open end and a closed end, saidopen end being defined by a circumferential edge, said circumferentialedge lying in a first plane, said cap portion being configured such thatthe greatest straight line distance connecting two points on saidcircumferential edge of said body portion is greater than theperpendicular distance between said second plane of said body portionand a second plane of the cap portion which contacts an outer surface ofthe closed end of the cap portion and which is parallel to the firstplane of the cap portion.
 3. The method as claimed in claim 2, whereinsaid tableted medication occupies at least 35 percent of the volume ofthe closed capsule.
 4. The method as claimed in claim 3, wherein saidtableted medication occupies at least 50 percent of the volume of theclosed capsule.
 5. The method as claimed in claim 1, further comprisingapplying one or more coatings to the closed capsule.